Antioxidant in broccoli 'shows promise' as treatment for progeria

A new study finds that the nuclei of cells in children affected by the extremely rare
disease progeria are poor at breaking down and disposing of defective proteins. It also finds that
an antioxidant present in broccoli appears to give the protein-clearing system a boost,
potentially reducing the effects of the disease.

The progeria-diseased cell nucleus (left) is deformed compared with a normal cell nucleus (right) because it has higher levels of progerin. Blue is DNA and red is progerin.Image credit: K. Djabali / TUM.

Progeria - short for Hutchinson-Gilford progeria syndrome - is an extremely rare and fatal
genetic disorder where children appear to age prematurely because of a faulty protein in their
cell nuclei. As the defective protein - known as progerin - accumulates, it interferes with a
number of cell functions.

In the journal Aging Cell, researchers from the Technical University at Munich (TUM)
in Germany, describe how they succeeded in reducing levels of progerin in diseased cells by
reactivating a protein-clearing process. They did this using sulforaphane - an antioxidant found
in broccoli and other cruciferous vegetables, such as cabbage and Brussels sprouts.

For their study, the team - led by Karima Djabali, a professor in the TUM School of Medicine
and the Institute for Medical Engineering - compared progeria-diseased cells with healthy
cells to look for differences in the proteins in the cell nuclei.

Most progeria patients carry a faulty gene that produces a faulty version of a protein called
lamin A. This faulty version is what is known as progerin.

Normal lamin A is an important component of the matrix that surrounds DNA in the cell nucleus
and plays a key role in gene expression. But the progerin version of lamin A does not have a function; it just becomes a nuisance as it
accumulates because the cell continues to make it as instructed by the faulty gene.

However, as it collects in the nucleus, progerin causes the cell to "age," meaning
patients with the disease develop classic health problems of old age, such as atherosclerosis, osteoporosis, stroke and heart attack.

Using sophisticated protein analysis techniques - known as proteomics - the team compared the
diseased and normal cells and found a surprising similarity.

Healthy cells also produce progerin, but they eliminate it quickly

The healthy cells also contained progerin - but at much lower levels. It seems that progerin is
a natural byproduct in cells, but healthy cells get rid of it before it can accumulate to
dangerous levels, as Prof. Djabali explains:

"Progerin is also produced in healthy cells, probably as a byproduct. A well-functioning
cellular waste disposal system can break down these small quantities of progerin."

One of the main differences between the healthy and diseased cells was that levels of progerin
in the nuclei of diseased cells were 10-20 times higher than levels in the nuclei of
healthy cells. Thus, the nuclei of progeria-diseased cells appear to have a huge backlog of cell debris that is
not removed.

On further investigation, the team also found that the mechanism that removes debris from the
cell nucleus - known as ubiquitin-proteasome system and autophagy - did not work properly in the
progeria-diseased cells.

These debris-clearing systems comprise huge complexes of proteins that do not appear to be
produced in sufficient quantities in progeria-diseased cells.

Prof. Djabali says:

"These errors in the cellular debris disposal system enhance the effect
that progerin accumulates and causes cell damage within a short time."

Altogether, the team found the progeria-diseased cell nuclei had over 28 proteins - each
carrying out a number of cell functions - with faults in them, and all the faults came from the
same mutation of the lamin A gene.

Sulforaphane reactivated protein and debris elimination in the cell nuclei

In the second part of the study, the team searched the literature for substances that might
activate the debris-clearing system in the cell nuclei and help rid the diseased cells of excess
progerin.

That is how they found the antioxidant sulforaphane - a substance present in broccoli and other
members of the crucifer family - that activates debris elimination in cells.

When the researchers treated progeria-diseased cells with sulforaphane, they found it
significantly reduced levels of progerin in their nuclei. Diseased cells treated with sulforaphane also appeared to have less DNA damage and nuclear
deformations, they note.

Prof. Djabali warns that it is early days and their experiments were "very basic," but the
study is a step toward developing an effective treatment for progeria, and it may also "help us
develop anti-aging strategies in the future," she adds.

Please note: If no author information is provided, the source is cited instead.

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